13-polycarbonalkyl-17-hydroxygona-17-nitrite esters



United States Patent O US. Cl. 260-3974 11 Claims ABSTRACT OF THE DISCLOSURE The compounds of the class of 13-polycarbonalkyl-17- hydroxygona-17-nitrite esters useful as hypotensive agents.

BACKGROUND OF THE INVENTION This invention relates to the field of new physiologically active 13 polycarbonalkyl-l7-hydroxygonane, 17-nitrite esters and novel processes for their preparation.

The preparation of l7-nitrite estrane and l7-nitrite androstane esters having estrogenic and cholesterol lowering properties is disclosed by E. P. Oliveto in US. Patent 3,127,406.

SUMMARY OF THE INVENTION More particularly, this invention is directed to compounds of the formulae:

ONO

wherein (E) represents the alpha or beta position; R is selected from the group consisting of alkyl of less than carbon atoms and cycloalkyl of 5 to 6 carbon atoms; R is an alkyl group of 2 to 5 carbon atoms; R is selected from the group consisting of hydrogen and alkyl of less than 5 carbon atoms; W is selected from the group consisting of a double-bond and a saturated linkage between C4 and C5; W is selected from the group consisting of a double-bond and a saturated linkage between C6 and C7; and W is selected from the group consisting of a double-bond and a saturated linkage between C9 and C10.

The final product of this invention are physiologically active substances which are useful as hypotensive agents.

The compounds of the present invention can be prepared and administered to warm-blooded animals in a wide variety of oral and parenteral dosage forms.

For preparing pharmaceutical compositions from the physiologically active compounds of this invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet-disintegrating agents: it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided compound. In the tablet the compound is mixed with carrier having the necessary binding properties in sutiable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 10 to 99% of the active Oil 3,492,320 Patented Jan. 27, 1970 ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin tragacanth methyl cellulose sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term preparation is intended to include the formulation of the compound with encapsulating material as carrier providing a capsule in which the compound (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets and capsules can be used for oral administration.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solutions. Aqueous suspensions suitable for oral use can be made by'dispensing the finely divided compound in water with viscous material, natural or synthetic gums, resins, etc., forexample, gum arabic, ion-exchange resins, methyl cellulose, sodium carboxymethyl cellulose and other well known suspending agents.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is sub-divided in unit doses containing appropriate quantities of the compound, the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted powders of vials or ampules.

The unit dosage form can be a capsule, cachet or tablet itself or it can be the appropriate number of any of those in package form. The quantity of compound in a unit dose of preparation may be varied or adjusted from a 1 mg. to mg. according to the particular application and the potency of the active ingredient.

In therapeutic use, the preparations are administered at the initial dosage of about 5 mg. to 25 mg. per kilogram daily. The dosages, however, may be varied depending upon the requirements of the patient.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of this invention may be prepared according to the process of this invention which may be represented by the following reaction scheme wherein R R W, W and W are as hereinbefore defined:

According to one feature of this invention l3-polycarbonalkyl-17-hydroxygon-3-one compounds of the Formula I are treated with nitrosyl chloride in a basic organic solvent, such as pyridine, to yield the l3-polycarbonalkyll7-hydroxy-3-one, l7-nitrite esters of Formula II.

The initial 13 polycarbonalkyl-17-hydroxygon-3-one compounds (I) may be prepared in accordance with any prior art processes such as described by G. A. Hughes et al. in US. Patent 3,202,686, G. C. Buzby et al. in J. of Med. Chem. 9, 338-341 (1966) and H. Smith et al. in J. Chem. Soc. 4472 (1964).

In accordance with another feature of this invention 13- polycarbonalkyl 17 hydroxy-8()-3-alkoxygona-l,3,5 (10)-triene compounds may be similarly treated with nitrosyl chloride in a basic organic solvent to yield the corresponding l7-nitrite esters.

These initial 13 polycarbonalkyl-l7-hydroxy-8()-3- alkoxygona-1,3,5()-triene compounds may be prepared by any conventional process such as described in said US. Patent 3,202,686 and said J. of Med. Chem.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 13-ethyl-3-methoxygona-1,3,5 10) -trienl7fi-ole, nitrite 10.0 gm. of 13-ethyl-3-methoxygona-1,3,5(10)-trien- 175-01 is dissolved in 250 ml. of pyridine and cooled to C. by immersion in a bath of ice-methanol. Nitrosyl chloride is passed as a gas through the solution for 1 hour. The resulting dark brown solution is stirred at -15 for an additional 1.5 hours and then poured onto 750 gm. of ice. The mixture is filtered and the resulting yellow solid is purified by dissolving in methylene chloride and treating with charcoal. The mixture is filtered and the solvent is evaporated in vacuo to yield 10.2 gm. of 13- ethyl-3-methoxygona-1,3,5(10)-trien-17B-ol, nitrite as a yellow solid; M.P. 89-93". Further purification by trituration with ethanol and filtration gives M.P. 94-97";

Analysis.-Calcd. for C H NO C, 72.92; H, 8.26; N, 4.25. Found: C, 73.19; H, 8.33; N, 4.27.

EXAMPLE 2 1 3-propy1-3 -methoxygona-1,3 ,5 (10) -trien-17,3-o1, nitrite Following the procedure of Example 1, but substituting 13-propyl-3-methoxygona-1,3,5(10)-trien-17p-ol for 13- ethyl-3-methoxygona-1,3,5(10)-trien-17B-ol there is obtained 13 propyl-3-methoxygona-l,3,5(10)-trien-l7fl-o1, nitrite.

EXAMPLE 3 1 3-buty1-3 -methoxygona-1 ,3,5 10) -trien-17fi-ol, nitrite Following the procedure of Example 1, but substituting 13 butyl 3-methoxygona-1,3,5(10)-trien-17fi-ol for 13- ethyl-3-methoxygona-1,3,5(10)-trien-17,B-ol there is obtained 13 butyl 3-methoxygona-l,3,5(10)-trien-17B-ol, nitrite.

EXAMPLE 4 13-isobutyl-3-methoxygona-1,3,5 10) -trien- 1713-01, nitrite Following the procedure of Example 1, but substituting 13-isobutyl-3-methoxygona-1,3,5 10) -trien- 175-01 for 1 3- ethy1-3-methoxygona-1,3,5-(10)-trien-17fi-o1 there is obtained 13-isobutyl-3methoxygona-1,3,5( 10) -trien-17fl-o1, nitrite.

EXAMPLE 5 13-ethyl-3-ethoxygona-1,3,5 10) -trien- 1 7 8-01, nitrite Following the procedure of Example 1, but substituting 13-ethyl-3-ethoxygona-l,3,5(10)-trien-17fl-ol for 13-ethyl- 3-methoxygona-1,3,5(10)-tricn-17fl-0l there is obtained 13-ethyl-3-ethoxygona-1,3,5 10)-trien-17p-ol, nitrite.

EXAMPLE 6 1 3-ethy1-3-propoxygona-1,3,5 10) -trien-17B-ol, nitrite Following the procedure of Example 1, but substituting 13 ethyl 3-propoxygona-1,3,5(10)-trien-17fl-ol for 13- ethyl-3-methoxygona-l,3,5(10)-trien-175-ol there is obtained 13 ethyl 3-propoxygona-1,3,5(10)-trien-17B-o1, nitrite.

EXAMPLE 7 1 3-propy1-3 -ethoxygon a-1,3,5 10) -trien- 17 (3-01, nitrite Following the procedure of Example 1, but substituting 13 propyl 3-ethoxygoua-1,3,5(10)-trien-l7fl-ol for 13- ethy1-3-methoxygona-l,3,5(10)-trien-17fi-ol there is obtained 13 propyl 3-ethoxygona-1,3,5-(10)-trien-175-0l, nitrite.

4 EXAMPLE 8 13-ethyl-3 -methoxy-8 a-gona-1,3 ,5( l0 -trien- 1778-01, nitrite Following the procedure of Example 1, but substituting l3-ethyl-3-methoxy-8u-gona-l,3,5(10)-trien-l7B-ol for 13- ethyl-3-methoxygona-1,3,5 (10)-trien 1718-01 there is obtained 13-ethyl-3-methoxy-8m-gona-l,3,5(10)-trien-17fi-ol, nitrite.

EXAMPLE 9 l3-propyl-3 -methoxy-8u-gona-1,3,5 10)-trien-17fi-0l,

nitrite Following the procedure of Example 1, but substituting l3 propyl-3-methoxy-8a-gona-1,3,5(10)-trien-17fi-ol for l3-ethyl-3-methoxygona-1,3,5(10)-trien-l7B-ol there is obtained 13-propyl-3-methoxy-8ot-gona-1,3 ,5 10)-trien-17B- ol-nitrite.

EXAMPLE 10 13-butyl-3-methoxy-8ot-gona-1,3 ,5 10) -trien- -01, nitrite Following the procedure of Example 1, but substituting 13-butyl-3-methoxy-8a-gona-l,3,5 10)-trien- 175-01 for 13- ethyl-S-methoxygona-1,3,5(10)-trien-l7fi-o1 there is obtained 13-butyl-3-meth0xy-8a-gona-1,3,5 (10)-trien-17B-ol, nitrite.

EXAMPLE 11 13-ethyl-3 -ethoxy-8a-gona-1,3 ,5 10) -trien- 1 718-01, nitrite Following the procedure of Example 1, but substituting 13-ethyl-3-ethoxy-8a-gona-1,3,5-trien-1713-01 for 13-ethyl- 3-ethoxy-Sa-gona-1,3,5(10)-trien-17B-ol, there is obtained 13-ethyl-3-ethoxy-8a-gona-l,3,5,( 10)-trien-17fi-o1, nitrile.

EXAMPLE 12 1 3-ethyl- 17 fi-hydroxygon-4-en-3-one, nitrite 5.0 gm. of l3-ethyl-17fl-hydroxygon-4-en-3-one is dissolved in 250 ml. of pyridine and cooled to -l5 C. in an ice-methanol bath. Nitrosyl chloride is passed as a gas through the solution for one hour. The reaction mixture is stirred at -15 for an additional 2 hours. The reaction mixture is then poured onto ice (1000 g), the precipitate is filtered and washed with ethanol to give 5.0 gm. of 13-ethyl-17fi-hydroxygon-4-en-3-0ne, nitrite; M.P. 119- 122;

6.0; and 6.13 kfiifl 238 me (e 18,700) Analysis.-Ca1cd. for C H No z C, 71.89; H, 8.57; N, 4.41. Found: C, 71.59; H, 8.47; N, 4.51.

EXAMPLE 13 13-propy1-17(i-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 12, but substituting 13 propyl 17,3-hydroxygon-4-en-3-one for 13-ethy1- 175-hydroxygon-4-en-3-one there is obtained 13-propyl- 17B-hydroxygon-4-en-3-one, nitrite.

Following the procedure of Example 12, but substituting 13-ethyl-1713-hydr0xygona-4,6-dien-3-0ne for 13-ethyl- 175-hydroxygon-4-en-3-one there is obtained 13-ethyl- 17fl-hydroxygona-4,6-dien-3-one, nitrite.

EXAMPLE 17 13-ethyl-17fi-hydroxygona-4,9-dien-3-one, nitrite Following the procedure of Example 12, but substituting, 13-ethyl-17fl-hydroxygona-4,9-dien-3-one for 13-ethyl- 17,8-hydroxygon-4-en-3-one there is obtained 13-ethyl-l7/8- hydroxygona-4,9-dien-3-one, nitrite.

EXAMPLE 18 1 3-ethyl- 17 fi-hydroxygonan-3-one, nitrite Following the procedure of Example 12, but substituting 13-ethyl-17fi-hydroxygonan-3-one for 13-ethyl-17 8- hydroxygon-4-en-3-one there is obtained 13-ethyl-l7fihydroxygonan-3-one, nitrite.

EXAMPLE 19 13,17rx-diethyl-l7fi-hydroxygon-4-en-3-one, nitrite m 5.95 and 6.19 A523? 238 m (6 18,200)

Analysis.-Calcd. for C H NO C, 73.00; H, 9.05. Found: C, 73.26; H, 9.04.

EXAMPLE 20 13-propyl-l7a-ethyl-l7B-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13-propyl-17a-ethyl-17,8-hydroxygon-4-en-3-one for 13,17a-diethyl-l7/8-hydroxygon-4-en-3-one there is obtained nitrite.

EXAMPLE 21 13-butyl-17a-ethyl-17/3-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13-butyl 17oz ethyl-17B-hydroxygon-4-en-3-one for 13,17a-diethyl-17/3-hydroxygon-4-en-3-one there is obtained 13-butyl 170a ethyl-l7fi-hydroxygon-4-en-3-one, nitrite.

EXAMPLE 22 13-isobutyl-17a-ethyl-17/3-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13 isobutyl-17a-ethyl-17 3-hydroxygon-4-en-3-one for 13,17a-diethyl-17fi-hydroxygon-4-en-3-one there is obtained l3-isobutyl 17a ethyl-17 3-hydroxygon-4-en-3- one, nitrite.

EXAMPLE 23 13-ethyl-l7a-methyl-17fl-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13-ethyl-17a-methyl-17B-hydroxygon-4-en-3-one for l3,17a-diethyl-17B-hydroxygon-4-en-3-one there is obtained 13 ethyl-17a-methyl-l7fi-hydroxygon-4-en-3-one, nitrite.

EXAMPLE 24 13-ethyl-17a-propyl-17fi-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13 ethyl-17a-propyl-175-hydroxygon-4-en-3-one for 13,170 diethyl-l7 3-hydroxygon-4-en-3-one there is obtained 13 ethyl-17a-propyl-17fi-hydroxygon-4-en-3-one, nitrite.

13 propyl-17a-ethyl-175-hytlroxv2on-4-en-3-nne.

6 EXAMPLE 25 13-ethyl-17a-butyl-17fl-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13-ethyl 17a butyl-17,8-hydroxygon-4-en-3-one for 13,17rx-diethyl-l7fl-hydroxygon-4-en-3-one there is obtained 13 ethyl 17 oz butyl-17B-hydroxygon-4-en-3-one, nitrite.

EXAMPLE 26 13-butyl-17a-methy1-17fl-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13-butyl-17a-methyl-l7fi-hydroxygon-4-en-3-one for 13,17u-diethyl-17fl-hydroxygon-4-en-3-one there is obtained 13 butyl-17a-methyl-l7 3-hydroxygon-4-en-3-one, nitrite.

EXAMPLE 27 13-propyl-17rx-butyl-17fl-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13 -pr0pyl-17u-butyl-17 3-hydroxygon-4-en-3-one for 13,17a-diethyl-17/i-hydroxygon-4-en-3-one there is obtained 13 propyl-17a-butyl-17 9-hydroxygon-4-en-3-one, nitrite.

EXAMPLE 28 13,l7rx-dipropyl-l7fl-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13,17a-dipropyl-l7fi-hydroxygon 4 en 3 one for 13,17a-diethyl-17/3-hydr0xygon-4-en-3-one there is obtained 13,17rx-dipropyl-17,8-hydroxygon-4-en-3-one, nitrite.

EXAMPLE 29 13,17a-dibutyl-17fi-hydroxygon-4-en-3-one, nitrite Following the procedure of Example 19, but substituting 13,17a-dibutyl-l7,6-hydroxygon-4-en-3-one for 13,17adiethyl 17B hydroxygon-4-en-3-one there is obtained 13,17a-dibutyl-17/8-hydroxygon-4-en-3-one, nitrite.

EXAMPLE 30 13,17wdiethyl-17p-hydroxygonan-3-one, nitrite Following the procedure of Example 19, but substituting l3,l7a-diethyl-17p-hydroxygonan-3-one for 13,17adiethyl 17/8 hydroxygon-4-en-3-one there is obtained 13,17a-diethyl-17fi-hydroxygonan-3-one, nitrite.

EXAMPLE 31 13,17a-diethyl-17 8-hydroxygona-4,6-dien-3-one, nitrite Following the procedure of Example 19, but substituting 13,17a-diethyl-l7B-hydroxygona-4,6-dien-3-one for 13,17a-diethy1-17B-hydroxygon-4-en-3-one there is obtained 13,17u-diethyl 17B hydroxygona-4,6-dien-3-one, nitrite.

EXAMPLE 32 13,17a-diethy1-17 8-hydroxygona-4,9-dien-3-one, nitrite Following the procedure of Example 19, but substituting 13,170:-diethyl-17/i-hydroxygona-4,9-dien-3-one for 13,17u-diethyl-17B-hydroxygon-4-en-3-one there is obtained 13,17rx-diethyl 17,8 hydroxygona-4,9-dien-3-one, nitrite.

EXAMPLE 33 13, 17u-diethyl-3-n1ethoxygona-1,3,5 10)-trien-17/9-ol, nitrite Following the procedure of Example 19, but substituting 13, l7a-diethyl-3-methoxygona-1,3,5 10) -trien-17fl-ol for 13,17a-diethyl-17 8-hydroxygon-4-en-3-one there is obtained 13, 17or-diethyl-3-methoxygona- 1,3,5 10)-trien-17fiol, nitrite.

EXAMPLE 34 13,17 a-dipropyl-3-methoxygona-1,3,5 10)-trien-17p-ol, nitrite 7 Following the procedure of Example 19, but substituting 13,17a-dipropyl-3-methoxygona-1,3,5 10)-trien-17B- 01 for 13,17a-diethyl-17I3-hydroxygon-4-en-3-one there is obtained 13,17a-dipropyl-3-methoxygona-1,3,5 10 -trien- 175-01, nitrite.

EXAMPLE 35 13 l7a-dibutyl-3-methoxygona- 1 ,3,5 1O -trien- 175-01, nitrite Following the procedure of Example 19, but substituting 13,17u-dibutyl-3-methoxygona-1,3,5( 10)-trien-175-ol for l3,l7u-diethyl-l7B-hydroxygon-4-en-3-one there is obtained 13,17a-dibutyl-3-methoxygona-1,3 ,5 l -trien-1 7B- 0], nitrite.

EXAMPLE 36 1 3,17a-diethyl-3-ethoxygona-1,3 ,5 10 -trien- 1 7 -0 I, nitrite Following the procedure of Example 19, but substituting 13,17a-diethyl 3 ethoxygona-1,3,5()-trien-l7p-ol for 13,17a-diethyl-17fl-hydroxygon-4en-3-one there is obtained l3,17oz-diethyl-3-ethoxygona-1,3,5(10)-trien-17B-ol, nitrite.

EXAMPLE 37 13,17u-diethyl-B-methoxy-8a-gona-1,3 ,5( l0 trien 175-01, nitrite Following the procedure of Example 19, but substituting 13,17 diethyl 3-methoxy-8a-gona-1,3,5(10)-trien- 175-01 for 13,17a diethyl-l7fl-hydroxygon-4-en-3-one there is obtained l3,17a-diethyl-3-methoxy-8nt-gona-l,3, 5 10 -trien-17,B-ol, nitrite.

EXAMPLE 38 13,17a-diethyl-3 -cyclopentoxygona- 1,3 ,5 10) trien- 17 [3- ol, nitrite and wherein R is selected from the group consisting of an alkyl of less than 5 carbon atoms and a cycloalkyl of 5 to 6 carbon atoms; R is an alkyl group of 2 to 5 carbon atoms; R is selected from the group consisting of hydrogen and an alkyl of less than 5 carbon atoms; W is selected from the group consisting of a double-bond and a saturated linkage between C4 and C5; W is selected from the group consisting of a double-bond and a saturated linkage between C6 and C7; and W is selected from the group consisting of a double-bond and a saturated linkage between C9 and C10; with the proviso that W, W and W together are selected from the group consisting of saturated linkages, a A linkage, a A linkage and a A linkage.

2. A compound according to claim 1 having the structural formula:

wherein R, R and R are as hereinbefore defined.

3. A compound according to claim 2 that is 13-ethyl- 3-methoxygona-1,3 ,5 10) -trien-l7p-ol, nitrite.

4. A compound according to claim 2 that is 13,17adiethyl-3-methoxygona-1,3,5 (10)-trien17 S-o1, nitrite.

5. A compound according to claim 2 that is l3-ethyl-3- methoxy-S a-gona-1,3,5 10)-trien-175-ol, nitrite.

6. A compound according to claim 1 having the structural formula:

References Cited UNITED STATES PATENTS 3/1964 Oliveto 260-287 OTHER REFERENCES Robinson et al., Journ. Amer. Chem. Soc., vol. 83, April 1961, pp. 1771-2.

Smith et al., Journ. Chem. Soc., November 1964, pp. 4472-4492, p. 4476.

Irmscher, Justus Liebigs Annalen der Chemie, Bd. 695, 1966, pp- 158463.

LEWIS GOTTS, Primary Examiner E. G. LOVE, Assistant Examiner US. Cl. X.R. 

